Reversing inflammatory macrophage activation as treatment for neonatal intraventricular hemorrhage and hydrocephalus

逆转炎症巨噬细胞活化治疗新生儿脑室内出血和脑积水

• 批准号: 9977341
• 负责人: BRANDON A MILLER
• 金额: $ 18.54万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9977341
• 关键词: Activation Analysis; Adult; Affect; Animals; Anti-Inflammatory Agents; Antibiotics; Antibodies; Azithromycin; Birth; Bone Marrow; Brain; Brain Injuries; Bromodeoxyuridine; Cell Communication; Cell Death; Cell Maturation; Cell Survival; Cell division; Cells; Central Nervous System Diseases; Cerebral Ventricles; Cerebrum; Child; Childhood Injury; Clinical; Clinical Research; Clinical Trials; Cognitive deficits; Data; Development; Dichloromethylene Diphosphonate; Disease; Failure; Goals; Hematogenous; Hemoglobin; Hemorrhage; Hydrocephalus; Immunochemistry; Immunohistochemistry; In Vitro; Infiltration; Inflammation; Inflammatory; Injections; Injury; Interruption; Intraventricular; Liquid substance; Macrophage Activation; Maps; Measures; Mediating; Medical; Messenger RNA; Microglia; Modeling; Myelin; Myelin Basic Proteins; Myelogenous; NF-kappa B; Neonatal; Neonatal Brain Injury; Nervous System Physiology; Neurological outcome; Nucleic Acids; Oligodendroglia; Outcome; Oxidative Stress; Oxides; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Premature Birth; Premature Infant; Process; Production; Property; Rattus; Recovery; Role; Site; Spinal cord injury; Stimulus; TNF gene; Testing; Therapeutic; Time; Tissues; Training; Ventricular; Western Blotting; Work; blood product; brain cell; cell type; central nervous system injury; chemokine; cytokine; disability; excitotoxicity; experimental study; functional improvement; improved; improved outcome; in vitro Model; in vivo; intraventricular hemorrhage; lateral ventricle; lung injury; mRNA Expression; macrophage; monocyte; myelination; neonatal brain; neonate; nervous system disorder; neurobehavioral; neuroinflammation; oligodendrocyte progenitor; pre-clinical; preservation; protein expression; recruit; repaired; response; self renewing cell; stem cells; white matter; white matter injury

Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagic hydrocephalus (PHH). Within the same time frame that neonatal IVH occurs, the neonatal brain is also rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors that are present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation causes OPC loss and failure of myelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophages are activated by many different stimuli in CNS injury and disease, including blood products released into the ventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes, as macrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibiotic properties, azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatory phenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety of anti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparing and neurological function. Importantly, azithromycin has already undergone rigorous clinical trials in neonates for inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages in IVH/PHH and test azithromycin’s ability to protect OPCs from macrophage-induced injury in a rat model of neonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activation, OPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to use neurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depth mechanistic studies of macrophage-OPC interaction. This project will support Dr. Miller’s training in studies of neuroinflammation and neurotherapeutics. If successful, this project will pave the way for clinical studies of azithromycin for improving neurological outcome after neonatal IVH.

新生儿脑室内出血（IVH）起源于发育不全的生殖基质， 大脑侧脑室附近的细胞快速分裂。IVH导致出血后 脑积水（PHH）。在新生儿IVH发生的同一时间段内，新生儿大脑也迅速 产生髓鞘形成所需的细胞。少突胶质细胞是大脑的髓鞘形成细胞， 来自少突胶质细胞祖细胞（OPCs）。OPCs是脆弱的细胞-对许多因素非常敏感， 存在于多种神经系统疾病中，如兴奋性毒性、炎性细胞因子和氧化性 应力在广泛的神经系统疾病中，神经炎症导致OPC丢失和功能障碍。 髓鞘形成浸润性脑巨噬细胞与许多形式的新生儿脑损伤有关。巨噬 在中枢神经系统损伤和疾病中，被许多不同的刺激物激活，包括释放到 心室间隙了解IVH后巨噬细胞的作用对改善结局至关重要， 巨噬细胞活化介导其它形式的新生儿脑损伤中的白色损伤。 阿奇霉素是一种常用的抗生素，对新生儿是安全的。除了抗生素 阿奇霉素也具有抗炎作用，并将巨噬细胞活化转化为抗炎作用。 表型，实际上促进组织恢复，而不是损伤。阿奇霉素已被用于各种 抗炎应用，包括在脊髓损伤中的临床前工作，其中它改善了组织保护 和神经功能。重要的是，阿奇霉素已经在新生儿中进行了严格的临床试验 治疗炎症引起的肺损伤这项研究将阻断浸润性巨噬细胞， IVH/PHH，并在大鼠模型中测试阿奇霉素保护OPCs免受巨噬细胞诱导的损伤的能力。 新生儿IVH我将使用体内和体外实验的组合来检查巨噬细胞活化， 有和没有阿奇霉素治疗的OPC死亡和髓鞘形成。我的活体研究可以让我们 神经行为结果来评估阿奇霉素的疗效，而我的体外模型将允许深入研究 巨噬细胞-OPC相互作用的机制研究。该项目将支持米勒博士在以下研究方面的培训： 神经炎症和神经治疗学。如果成功，该项目将为临床研究铺平道路。 阿奇霉素改善新生儿IVH后神经功能预后